Methods of manufacturing benzoquinoline compounds

ABSTRACT

The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediates thereof.

This application is a continuation of U.S. Ser. No. 14/551,909, filedNov. 24, 2014, which claims the benefit of priority of U.S. ProvisionalApplication No. 61/911,214, filed Dec. 3, 2013, the disclosures of whichare hereby incorporated by reference as if written herein in theirentireties.

Disclosed herein are methods of manufacturing benzoquinoline compounds,and intermediates thereof.

Tetrabenazine (Nitoman, Xenazine, Ro 1-9569),1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinoline,is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazineis commonly prescribed for the treatment of Huntington's disease (Savaniet al., Neurology 2007, 68(10), 797; and Kenney et al., Expert Review ofNeurotherapeutics 2006, 6(1), 7-17).

d₆-Tetrabenazine is a deuterated analog of tetrabenazine which hasimproved pharmacokinetic properties when compared to the non-deuterateddrug and is currently under clinical development. U.S. Pat. No.8,524,733.

Deuterium Kinetic Isotope Effect

Tetrabenazine is a VMAT2 inhibitor. The carbon-hydrogen bonds oftetrabenazine contain a naturally occurring distribution of hydrogenisotopes, namely ¹H or protium (about 99.9844%), ²H or deuterium (about0.0156%), and ³H or tritium (in the range between about 0.5 and 67tritium atoms per 10¹⁸ protium atoms). Increased levels of deuteriumincorporation may produce a detectable Deuterium Kinetic Isotope Effect(DKIE) that could affect the pharmacokinetic, pharmacologic and/ortoxicologic profiles of tetrabenazine in comparison with tetrabenazinehaving naturally occurring levels of deuterium.

Based on discoveries made in our laboratory, as well as considering theliterature, tetrabenazine is metabolized in humans at the isobutyl andmethoxy groups. The current approach reduces metabolism at some or allof these sites. Limiting the production of these metabolites has thepotential to decrease the danger of the administration of such drugs andmay even allow increased dosage and/or increased efficacy. All of thesetransformations can occur through polymorphically-expressed enzymes,exacerbating interpatient variability. Further, some disorders are besttreated when the subject is medicated around the clock or for anextended period of time. For all of the foregoing reasons, a medicinewith a longer half-life may result in greater efficacy and cost savings.Various deuteration patterns can be used to (a) reduce or eliminateunwanted metabolites, (b) increase the half-life of the parent drug, (c)decrease the number of doses needed to achieve a desired effect, (d)decrease the amount of a dose needed to achieve a desired effect, (e)increase the formation of active metabolites, if any are formed, (f)decrease the production of deleterious metabolites in specific tissues,and/or (g) create a more effective drug and/or a safer drug forpolypharmacy, whether the polypharmacy be intentional or not. Thedeuteration approach has demonstrated the ability to slow the metabolismof tetrabenazine and attenuate interpatient variability.

Novel methods of manufacturing benzoquinoline compounds, includingtetrabenazine and deuterated tetrabenazine analogs such asd₆-tetrabenazine are disclosed herein.

In certain embodiments of the present invention, disclosed herein is aprocess of preparing a compound of Formula IV:

or a salt thereof, comprising:

-   -   a step of reacting a compound of Formula II or a salt thereof        with a compound of Formula III:

-   -   in the presence of a base;    -   wherein:    -   R₇-R₁₂ and R₁₅ are independently selected from the group        consisting of hydrogen and deuterium; and    -   Y₁ is selected from the group consisting of acetoxy, alkoxy,        halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy, and aryloxy,        any of which may be optionally substituted.

In certain embodiments, Y₁ is acetoxy.

In certain embodiments, Y₁ is C₁-C₄ alkoxy.

In certain embodiments, Y₁ is ethoxy.

In certain embodiments, Y₁ is selected from the group consisting offluorine, chlorine, and bromine.

In certain embodiments, said base is selected from the group consistingof alkali metal alkoxides, alkali metal hydroxides, alkali metalhydrides, alkali metal carbonates, and trialkylamines.

In certain embodiments, said base is an alkali metal alkoxide.

In certain embodiments, said base is sodium tert-butoxide.

In certain embodiments, Y₁ is ethoxy.

In certain embodiments, disclosed herein is a process of preparing acompound of Formula VI:

comprising:

-   -   a step of reacting a compound of Formula IV or a salt thereof        with a compound of Formula V:

-   -   in a solvent and in the presence of a base;    -   wherein:    -   R₁-R₁₂ and R₁₅ are independently selected from the group        consisting of hydrogen and deuterium; and    -   Y₂ is selected from the group consisting of halogen, alkyl        sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate,        aryl sulfonate, alkylaryl sulfonate, dialkyloxonium,        alkylphosphate, and alkylcarbonate, any of which may be        optionally substituted.

In certain embodiments, Y₂ is iodide or methylsulfate.

In certain embodiments, Y₂ is iodide.

In certain embodiments, said base is selected from the group consistingof alkali metal carbonates, alkali metal bicarbonates, alkali metalalkoxides, alkali metal hydroxides, alkali metal hydrides, andtrialkylamines.

In certain embodiments, said base is an alkali metal carbonate.

In certain embodiments, said base is potassium carbonate.

In certain embodiments, said solvent is selected from the groupconsisting of acetone, acetonitrile, dimethyl formamide,2-methyltetrahydrofuran, and tetrahydrofuran.

In certain embodiments, said solvent is acetone.

In certain embodiments, the volume of said solvent is between about 5 toabout 15 times the mass of the compound of Formula IV.

In certain embodiments, the volume of said solvent is between about 6 toabout 10 times the mass of the compound of Formula IV.

In certain embodiments, the volume of said solvent is about 8 times themass of the compound of Formula IV.

In certain embodiments, said reaction step is carried out in thepresence of a phase transfer catalyst.

In certain embodiments, said phase transfer catalyst is selected fromthe group consisting of tetrabutylammonium bromide, tetrabutylammoniumiodide, and 18-crown-6.

In certain embodiments, said phase transfer catalyst istetrabutylammonium bromide.

In certain embodiments, disclosed herein is a process of preparing asolid salt of a compound of Formula VII:

comprising:

-   -   a first step of reacting a compound of Formula VI:

-   -   with a dehydrating agent in a reaction solvent;    -   a second step of adding a quenching solvent and an antisolvent        to the reaction mixture; and    -   a third step of isolating the salt of the compound of Formula        VII from the reaction mixture;    -   wherein:    -   R₁-R₁₂ and R₁₅ are independently selected from the group        consisting of hydrogen and deuterium.

In certain embodiments, said salt of the compound of Formula I is thehydrochloride salt.

In certain embodiments, said dehydrating agent is selected from thegroup consisting of phosphorous oxychloride, phosphorus pentachloride,and thionyl chloride.

In certain embodiments, the amount of said phosphorous oxychloride isbetween about 0.5 to about 4 molar equivalents relative to the compoundof Formula VI.

In certain embodiments, the amount of said phosphorous oxychloride isbetween about 1.6 to about 2.0 molar equivalents relative to thecompound of Formula VI.

In certain embodiments, the amount of said phosphorous oxychloride isabout 1.8 molar equivalents relative to the compound of Formula VI.

In certain embodiments, said reaction solvent is selected from the groupconsisting of methyl tert-butyl ether, toluene, and acetonitrile.

In certain embodiments, said reaction solvent is acetonitrile.

In certain embodiments, the volume of said acetonitrile is between about1 to about 4 times the mass of the compound of Formula VI.

In certain embodiments, the volume of said acetonitrile is between about1.5 to about 2.5 times the mass of the compound of Formula VI.

In certain embodiments, the volume of said acetonitrile is about 2 timesthe mass of the compound of Formula VI.

In certain embodiments, said quenching solvent is anprotic solventsselected from the group consisting of water, an alcohol, and a proticacid.

In certain embodiments, said quenching solvent is selected from thegroup consisting of ethanol, 1-propanol, isopropanol, 1-butanol,2-methylpropanol, tert-butanol, and 1-pentanol.

In certain embodiments, said quenching solvent is 1-butanol.

In certain embodiments, the amount of said 1-butanol is between about 2to about 8 molar equivalents relative to the compound of Formula VI.

In certain embodiments, the amount of said 1-butanol is between about2.4 to about 6 molar equivalents relative to the compound of Formula VI.

In certain embodiments, the amount of said 1-butanol is between about3.4 to about 4.2 molar equivalents relative to the compound of FormulaVI.

In certain embodiments, the amount of said 1-butanol is about 3.8 molarequivalents relative to the compound of Formula VI.

In certain embodiments, said quenching solvent is selected from thegroup consisting of hydrogen chloride, hydrogen bromide, hydrogeniodide, phosphoric acid, sulfuric acid, methanesulfonic acid, formicacid, acetic acid, and trifluoroacetic acid.

In certain embodiments, said antisolvent is selected from the groupconsisting of methyl tert-butyl ether, ethyl acetate, isopropyl acetate,2-methyltetrahydrofuran, diethyl ether, toluene, hexane, pentane, andcyclohexane.

In certain embodiments, said antisolvent is methyl tert-butyl ether.

In certain embodiments, the volume of said methyl tert-butyl ether isbetween about 1 to about 10 times the mass of the compound of FormulaVI.

In certain embodiments, the volume of said methyl tert-butyl ether isbetween about 3 to about 5 times the mass of the compound of Formula VI.

In certain embodiments, the volume of said methyl tert-butyl ether isabout 4 times the mass of the compound of Formula VI.

In certain embodiments, said first reaction step is carried out atreflux.

In certain embodiments, said first reaction step is held at atemperature of between about 0° C. to about 100° C.

In certain embodiments, said first reaction step is held at atemperature of between about 75° C. to about 95° C.

In certain embodiments, said first reaction step is held at atemperature of between about 80° C. to about 85° C.

In certain embodiments, said first reaction step is held at atemperature of between about 80° C. to about 85° C. for about 2 hours.

In certain embodiments, after said first reaction step is heated tobetween about 80° C. to about 85° C., the reaction mixture is cooled toa temperature between about 25° C. to about 35° C.

In certain embodiments, said second reaction step is carried out atbetween about 0° C. to about 100° C.

In certain embodiments, said second reaction step is carried out atbetween about 10° C. to about 50° C.

In certain embodiments, said second reaction step is carried out atbetween about 25° C. to about 35° C.

In certain embodiments, the reaction mixture is held at a temperaturebetween about 25° C. to about 35° C. for about 12 hours after theaddition of said quenching solvent and said antisolvent.

In certain embodiments, said salt of the compound of Formula VII isisolated by filtration.

In certain embodiments, disclosed herein is a process of purifying ahydrochloride salt of a compound of Formula VII:

comprising:

-   -   a first step of mixing the compound of Formula VII with one or        more solvents; and    -   a second step of filtering the salt of the compound of Formula        VII from the mixture;    -   wherein:    -   R₁-R₁₂ and R₁₅ are independently selected from the group        consisting of hydrogen and deuterium.

In certain embodiments, said solvent is selected from the groupconsisting of ethanol, 1-propanol, isopropanol, 2-methylpropanol,tert-butanol, 1-butanol, 1-pentanol, acetone, acetonitrile, ethylacetate, methyl tert-butyl ether, hydrogen chloride, hydrogen bromide,hydrogen iodide, phosphoric acid, sulfuric acid, methanesulfonic acid,formic acid, acetic acid, and trifluoroacetic acid.

In certain embodiments, said solvent is a mixture of ethanol and methyltert-butyl ether.

In certain embodiments, said solvent is a mixture of 10% ethanol and 90%methyl tert-butyl ether.

In certain embodiments, said first mixing step is carried out at betweenabout 0° C. to about 60° C.

In certain embodiments, said first mixing step is carried out at betweenabout 20° C. to about 40° C.

In certain embodiments, said first mixing step is carried out at betweenabout 28° C. to about 32° C.

In certain embodiments, disclosed herein is a process of preparing acompound of Formula IX:

comprising:

-   -   a step of reacting a compound of Formula VII or a salt thereof        with a compound of Formula VIII in one or more solvents:

-   -   wherein:    -   R₁-R₂₇ are independently selected from the group consisting of        hydrogen and deuterium; and X is selected from the group        consisting of halogen, alkyl sulfate, alkyl sulfonate,        halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl        sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate,        any of which may be optionally substituted.

In certain embodiments, said solvent is selected from the groupconsisting of water, methanol, and ethanol.

In certain embodiments, said solvent is a mixture of methanol and water.

In certain embodiments, said methanol and water mixture is between aboutfive parts methanol to one part water and about one part methanol to onepart water.

In certain embodiments, said methanol and water mixture is between aboutfour parts methanol to one part water and about two parts methanol toone part water.

In certain embodiments, said methanol and water mixture is about threeparts methanol to one part water.

In certain embodiments, the volume of said mixture of methanol and wateris between about 2 and about 10 times the mass of the compound ofFormula VII.

In certain embodiments, the volume of said mixture of methanol and wateris between about 4 and about 8 times the mass of the compound of FormulaVII.

In certain embodiments, the volume of said mixture of methanol and wateris about 6 times the mass of the compound of Formula VII.

In certain embodiments, said solvent is a mixture of ethanol and water.

In certain embodiments, said ethanol and water mixture is between aboutfive parts ethanol to one part water and about one part ethanol to onepart water.

In certain embodiments, said ethanol and water mixture is between aboutfour parts ethanol to one part water and about two parts ethanol to onepart water.

In certain embodiments, said ethanol and water mixture is about threeparts ethanol to one part water.

In certain embodiments, the volume of said mixture of ethanol and wateris between about 2 and about 10 times the mass of the compound ofFormula VII.

In certain embodiments, the volume of said mixture of ethanol and wateris between about 4 and about 8 times the mass of the compound of FormulaVII.

In certain embodiments, the volume of said mixture of ethanol and wateris about 6 times the mass of the compound of Formula VII.

In certain embodiments, said reaction step is held at a temperature ofbetween about 0° C. to about 100° C.

In certain embodiments, said reaction step is held at a temperature ofbetween about 25° C. to about 70° C.

In certain embodiments, said reaction step is held at a temperature ofbetween about 40° C. to about 60° C.

In certain embodiments, said reaction step is held at a temperature ofbetween about 45° C. to about 50° C.

In certain embodiments, said reaction step is carried out for about 1 toabout 96 hours.

In certain embodiments, said reaction step is carried out for about 24to about 72 hours.

In certain embodiments, said reaction step is carried out for about 48hours.

In certain embodiments, wherein the compound of Formula VII is thehydrochloride salt and a base is added during the reaction step.

In certain embodiments, said base is selected from the group consistingof alkali metal carbonates, alkali metal bicarbonates, alkali metalalkoxides, alkali metal hydroxides, alkali metal hydrides, andtrialkylamines.

In certain embodiments, said base is an alkali metal carbonate.

In certain embodiments, said base is potassium carbonate.

In certain embodiments, disclosed herein is a process of preparing acompound of Formula XI:

comprising:

-   -   a first step of reacting a compound of Formula X or a salt        thereof with a base in one or more solvents:

-   -   a second step of adjusting the pH of the reaction mixture by        addition of an acid;    -   a third step of adding dimethylamine or a salt thereof and a        formaldehyde equivalent to the reaction mixture;    -   a fourth step of lowering the pH of the reaction mixture by        addition of an acid;    -   a fifth step of raising the pH of the reaction mixture by        addition of an base;    -   a sixth step of adding dimethylamine or a salt thereof to the        reaction mixture;    -   wherein:    -   R₁₆-R₂₇ are independently selected from the group consisting of        hydrogen and deuterium.

In certain embodiments, the base used in the first hydrolysis step orthe fifth pH adjustment step is selected from the group consisting ofalkali metal carbonates and alkali metal hydroxides.

In certain embodiments, said base is an alkali metal hydroxide.

In certain embodiments, said base is potassium hydroxide.

In certain embodiments, said dimethylamine is dimethylaminehydrochloride.

In certain embodiments, said formaldehyde equivalent is selected fromthe group consisting of formaldehyde, aqueous formaldehyde solution,paraformaldehyde, and trioxane.

In certain embodiments, said formaldehyde equivalent is aqueousformaldehyde solution.

In certain embodiments, the acid used in the second pH adjustment stepor the fourth pH adjustment step is selected from the group consistingof hydrochloric acid, sulfuric acid, phosphoric acid, andmethanesulfonic acid.

In certain embodiments, said acid is hydrochloric acid.

In certain embodiments, a phase transfer catalyst is added during thethird reaction step.

In certain embodiments, said phase transfer catalyst istetrabutylammonium bromide.

In certain embodiments, the amount of said tetrabutylammonium bromide isabout 0.1 molar equivalents relative to said compound of Formula X.

In certain embodiments, said solvent is water.

In certain embodiments, the first hydrolysis step is carried out by theaddition of about 1 to about 2 molar equivalents of potassium hydroxiderelative to said compound of Formula X.

In certain embodiments, the first hydrolysis step is carried out by theaddition of about 1 to about 1.2 molar equivalents of potassiumhydroxide relative to said compound of Formula X.

In certain embodiments, the first hydrolysis step is carried out by theaddition of about 1.1 molar equivalents of potassium hydroxide relativeto said compound of Formula X.

In certain embodiments, the first hydrolysis step is carried out at atemperature of between about 0° C. to about 100° C.

In certain embodiments, the first hydrolysis step is carried out at atemperature of between about 20° C. to about 40° C.

In certain embodiments, the second pH adjustment step results in a pH ofabout 6 to about 8.

In certain embodiments, the second pH adjustment step results in a pH ofabout 6.8 to about 7.2.

In certain embodiments, the second pH adjustment step is carried out ata temperature of between about 10° C. to about 60° C.

In certain embodiments, the third addition step is carried out by theaddition of about 1 to about 2 molar equivalents of dimethylamine andformaldehyde equivalents relative to said compound of Formula X.

In certain embodiments, the third addition step is carried out by theaddition of about 1.25 to about 1.75 molar equivalents of dimethylamineand about 1.25 to about 1.75 molar equivalents of formaldehydeequivalents relative to said compound of Formula X.

In certain embodiments, the third addition step is carried out by theaddition of about 1.5 molar equivalents of dimethylamine and about 1.68molar equivalents of formaldehyde equivalents relative to said compoundof Formula X.

In certain embodiments, the third addition step is carried out at atemperature of between about 10° C. to about 60° C.

In certain embodiments, the third addition step is carried out at atemperature of between about 25° C. to about 35° C.

In certain embodiments, the reaction temperature is maintained for about1 to about 24 hours after third addition step.

In certain embodiments, the reaction temperature is maintained for about9 to about 15 hours after third addition step.

In certain embodiments, the reaction temperature is maintained for about12 hours after third addition step.

In certain embodiments, the fourth pH adjustment step results in a pH ofless than 3.

In certain embodiments, the fourth pH adjustment step results in a pH ofless than 1.

In certain embodiments, the fourth pH adjustment step is carried out ata temperature of between about 10° C. to about 60° C.

In certain embodiments, the fourth pH adjustment step is carried out ata temperature of between about 25° C. to about 35° C.

In certain embodiments, the fifth pH adjustment step results in a pH ofgreater than 10.

In certain embodiments, the fifth pH adjustment step results in a pH ofabout 12 to about 13.

In certain embodiments, the fifth pH adjustment step is carried out at atemperature of between about 10° C. to about 60° C.

In certain embodiments, the fifth pH adjustment step is carried out at atemperature of between about 25° C. to about 35° C.

In certain embodiments, the sixth addition step is carried out by theaddition of about 1 to about 2 molar equivalents of dimethylaminerelative to said compound of Formula X.

In certain embodiments, the sixth addition step is carried out by theaddition of about 1.25 to about 1.75 molar equivalents of dimethylaminerelative to said compound of Formula X.

In certain embodiments, the sixth addition step is carried out by theaddition of about 1.5 molar equivalents of dimethylamine relative tosaid compound of Formula X.

In certain embodiments, the sixth addition step is carried out at atemperature of between about 10° C. to about 60° C.

In certain embodiments, the sixth addition step is carried out at atemperature of between about 25° C. to about 35° C.

In certain embodiments, the reaction temperature is maintained for about1 to about 96 hours after third addition step.

In certain embodiments, the reaction temperature is maintained for about24 to about 48 hours after third addition step.

In certain embodiments, the reaction temperature is maintained for about36 hours after third addition step.

The compounds as disclosed herein may also contain less prevalentisotopes for other elements, including, but not limited to, ¹³C or ¹⁴Cfor carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen, and ¹⁷O or¹⁸O for oxygen.

All publications and references cited herein are expressly incorporatedherein by reference in their entirety. However, with respect to anysimilar or identical terms found in both the incorporated publicationsor references and those explicitly put forth or defined in thisdocument, then those terms definitions or meanings explicitly put forthin this document shall control in all respects.

As used herein, the terms below have the meanings indicated.

The singular forms “a,” “an,” and “the” may refer to plural articlesunless specifically stated otherwise.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “n₁-n₂” is used, where n₁ and n₂ are the numbers, then unlessotherwise specified, this notation is intended to include the numbersthemselves and the range between them. This range may be integral orcontinuous between and including the end values.

The term “deuterium enrichment” refers to the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat the specified position. Because the naturally occurring distributionof deuterium is about 0.0156%, deuterium enrichment at any position in acompound synthesized using non-enriched starting materials is about0.0156%. The deuterium enrichment can be determined using conventionalanalytical methods known to one of ordinary skill in the art, includingmass spectrometry and nuclear magnetic resonance spectroscopy.

The term “is/are deuterium,” when used to describe a given position in amolecule such as R₁-R₂₇ or the symbol “D”, when used to represent agiven position in a drawing of a molecular structure, means that thespecified position is enriched with deuterium above the naturallyoccurring distribution of deuterium. In one embodiment deuteriumenrichment is no less than about 1%, in another no less than about 5%,in another no less than about 10%, in another no less than about 20%, inanother no less than about 50%, in another no less than about 70%, inanother no less than about 80%, in another no less than about 90%, or inanother no less than about 98% of deuterium at the specified position.

The term “isotopic enrichment” refers to the percentage of incorporationof a less prevalent isotope of an element at a given position in amolecule in the place of the more prevalent isotope of the element.

The term “non-isotopically enriched” refers to a molecule in which thepercentages of the various isotopes are substantially the same as thenaturally occurring percentages.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as D-isomers and L-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The terms “3S,11bS enantiomer” or the term “3R,11bR enantiomer” refersto either of the d₆-tetrabenazine stereoisomers having the structuralformulas shown below:

In certain embodiments, a chemical structure may be drawn as either the3S,11bS enantiomer or the 3R,11bR enantiomer, but the text of thespecification may indicate that the 3S,11bS enantiomer, the 3R,11bRenantiomer, a racemic mixture thereof (which may be described as (RR,SS)-d6-tetrabenazine), or all of the foregoing may be intended to bedescribed.

The terms “(3S, 11bS)-enantiomer” or “(3R, 11bR)-enantiomer” or the asapplied to a compound of Formula I refers to either of the stereoisomersof compounds of Formula I shown below:

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, any of which may themselves beoptionally substituted. Additionally, R and R′ may combine to formheterocycloalkyl, either of which may be optionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHC₁—) and the like.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO₃H group and its anion or the—SO₃— group.

The terms “sulfate,” “sulfuric acid,” and “sulfuric,” as used herein,alone or in combination, refer the HOS(═O)₂OH group and its mono- ordianion or the —SO₄— group.

The terms “phosphate,” “phosphoric acid,” and “phosphoric,” as usedherein, alone or in combination, refer the P(═O)(OH)₃ group and itsmono-, di, or trianion or the —PO₄— group.

The terms “carbonate,” as used herein, alone or in combination, referthe —OC(═O)O— group.

The term “VMAT2” refers to vesicular monoamine transporter 2, anintegral membrane protein that acts to transport monoamines—particularlyneurotransmitters such as dopamine, norepinephrine, serotonin, andhistamine—from cellular cytosol into synaptic vesicles.

The term “VMAT2-mediated disorder,” refers to a disorder that ischaracterized by abnormal VMAT2 activity. A VMAT2-mediated disorder maybe completely or partially mediated by modulating VMAT2. In particular,a VMAT2-mediated disorder is one in which inhibition of VMAT2 results insome effect on the underlying disorder e.g., administration of a VMAT2inhibitor results in some improvement in at least some of the patientsbeing treated.

The term “VMAT2 inhibitor”, “inhibit VMAT2”, or “inhibition of VMAT2”refers to the ability of a compound disclosed herein to alter thefunction of VMAT2. A VMAT2 inhibitor may block or reduce the activity ofVMAT2 by forming a reversible or irreversible covalent bond between theinhibitor and VMAT2 or through formation of a noncovalently boundcomplex. Such inhibition may be manifest only in particular cell typesor may be contingent on a particular biological event. The term “VMAT2inhibitor”, “inhibit VMAT2”, or “inhibition of VMAT2” also refers toaltering the function of VMAT2 by decreasing the probability that acomplex forms between a VMAT2 and a natural substrate

VMAT2-mediated disorders include, but are not limited to chronichyperkinetic movement disorders, which can be psychogenic (e.g., tics),idiopathic (as in, e.g., Tourette's syndrome and Parkinson's Disease,genetic (as in, e.g., the chorea characteristic of Huntington'sDisease), infectious (as in, e.g., Sydenham's Chorea), or, drug induced,as in tardive dyskinesia. Unless otherwise stated, “chronic hyperkineticmovement disorders” refers to and includes all psychogenic, idiopathic,genetic, and drug-induced movement disorders. VMAT2 disorders alsoinclude disoders such as oppositional defiant disorder.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The term “therapeutically acceptable salt,” as used herein,represents salts or zwitterionic forms of the compounds disclosed hereinwhich are therapeutically acceptable as defined herein. The salts can beprepared during the final isolation and purification of the compounds orseparately by reacting the appropriate compound with a suitable acid orbase. Therapeutically acceptable salts include acid and basic additionsalts. For a more complete discussion of the preparation and selectionof salts, refer to “Handbook of Pharmaceutical Salts, Properties, andUse,” Stah and Wermuth, Ed., (Wiley-VCH and VHCA, Zurich, 2002) andBerge et al., J. Pharm. Sci. 1977, 66, 1-19.

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical composition. Accordingly, provided herein arepharmaceutical compositions which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, prodrugs, or solvates thereof, together with one or morepharmaceutically acceptable carriers thereof and optionally one or moreother therapeutic ingredients. Proper formulation is dependent upon theroute of administration chosen. Any of the well-known techniques,carriers, and excipients may be used as suitable and as understood inthe art; e.g., in Remington's Pharmaceutical Sciences. Thepharmaceutical compositions disclosed herein may be manufactured in anymanner known in the art, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or compression processes. The pharmaceuticalcompositions may also be formulated as a modified release dosage form,including delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art (see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugsand the Pharmaceutical Science, Marcel Dekker, Inc., New York, N.Y.,2002; Vol. 126).

General Synthetic Methods for Preparing Compounds

Isotopic hydrogen can be introduced into a compound as disclosed hereinby synthetic techniques that employ deuterated reagents, wherebyincorporation rates are pre-determined; and/or by exchange techniques,wherein incorporation rates are determined by equilibrium conditions,and may be highly variable depending on the reaction conditions.Synthetic techniques, where tritium or deuterium is directly andspecifically inserted by tritiated or deuterated reagents of knownisotopic content, may yield high tritium or deuterium abundance, but canbe limited by the chemistry required. Exchange techniques, on the otherhand, may yield lower tritium or deuterium incorporation, often with theisotope being distributed over many sites on the molecule.

The compounds as disclosed herein can be prepared by methods known toone of skill in the art and routine modifications thereof, and/orfollowing procedures similar to those described in the Example sectionherein and routine modifications thereof, and/or procedures found in WO2005077946; WO 2008/058261; EP 1716145; Lee et al., J. Med. Chem., 1996,(39), 191-196; Kilbourn et al., Chirality, 1997, (9), 59-62; Boldt etal., Synth. Commun., 2009, (39), 3574-3585; Rishel et al., J. Org.Chem., 2009, (74), 4001-4004; DaSilva et al., Appl. Radiat. Isot., 1993,44(4), 673-676; Popp et al., J. Pharm. Sci., 1978, 67(6), 871-873;Ivanov et al., Heterocycles 2001, 55(8), 1569-1572; U.S. Pat. Nos.2,830,993; 3,045,021; WO 2007130365; WO 2008058261, which are herebyincorporated in their entirety, and references cited therein and routinemodifications thereof. Compounds as disclosed herein can also beprepared as shown in any of the following schemes and routinemodifications thereof.

The following schemes can be used to practice the present invention. Anyposition shown as hydrogen may optionally be replaced with deuterium.

Compound 1 is reacted with compound 2, wherein Y₁ is selected from thegroup consisting of acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy,heteroalkoxy, and aryloxy, any of which may be optionally substituted,in the presence of an appropriate basic catalyst, such as sodiumtert-butoxide, at an elevated temperature to give compound 3. Compound 3is reacted with compound 4 in the presence of an appropriate base, suchas potassium carbonate, in an appropriate solvent, such as acetone, toafford compound 5. Compound 5 is reacted with an appropriate dehydratingagent, such as phosphorous oxychloride, in an appropriate solvent, suchas acetonitrile, at an elevated temperature to give compound 6. Compound7 is reacted with an appropriate methylating agent, such as methyliodide, in an appropriate solvent, such as methyl tert-butyl ether, atan elevated temperature to give compound 8. Compound 6 is reacted withcompound 8, in the presence of an appropriate base, such as potassiumcarbonate, in an appropriate solvent, such as a mixture of methanol andwater, at an elevated temperature to afford compound 9 of Formula I.Compound 9 may be optionally purified by recrystallization from anappropriate solvent, such as ethanol.

Deuterium can be incorporated to different positions synthetically,according to the synthetic procedures as shown in Scheme I, by usingappropriate deuterated intermediates. For example, to introducedeuterium at one or more positions of R₇-R₁₂, compound 1 with thecorresponding deuterium substitutions can be used. To introducedeuterium at R₁₅, compound 2 with the corresponding deuteriumsubstitution can be used. To introduce deuterium at one or morepositions of R₁-R₆, compound 4 with the corresponding deuteriumsubstitutions can be used. To introduce deuterium at one or morepositions of R₁₆-R₂₉, compound 7 with the corresponding deuteriumsubstitutions can be used.

Deuterium can also be incorporated to various positions having anexchangeable proton, via proton-deuterium equilibrium exchange.

Compound 10 is reacted with compound 11, in the presence of anappropriate base, such as potassium carbonate, an optional alkylationcatalyst, such as potassium iodide, and an optional phase transfercatalyst, such as tetrabutylammonium bromide, in an appropriate solvent,such as dimethylformamide, at an elevated temperature to give compound12. Compound 12 is reacted with an appropriate base, such as potassiumhydroxide, in an appropriate solvent, such as water, to afford anintermediate carboxylic acid which is further reacted with anappropriate secondary amine or salt thereof, such as dimethylaminehydrochloride, and an appropriate formaldehyde equivalent, such asaqueous formaldehyde solution, in the presence of an appropriate acid,such as hydrochloric acid, and an optional phase transfer catalyst, suchas tetrabutylammonium bromide, to give a mixture of compound 7 andcompound 13. The mixture of compound 7 and compound 13 is furtherreacted with an appropriate secondary amine or salt thereof, such asdimethylamine hydrochloride, in the presence of an appropriate base,such as potassium hydroxide, in an appropriate solvent, such as water,to give compound 7.

Deuterium can be incorporated to different positions synthetically,according to the synthetic procedures as shown in Scheme I, by usingappropriate deuterated intermediates. For example, to introducedeuterium at one or more positions of R₁₆-R₁₈, compound 10 with thecorresponding deuterium substitutions can be used. To introducedeuterium at one or more positions of R₁₉-R₂₇, compound 11 with thecorresponding deuterium substitutions can be used.

Deuterium can also be incorporated to various positions having anexchangeable proton, via proton-deuterium equilibrium exchange.

The invention is further illustrated by the following examples. AllIUPAC names were generated using CambridgeSoft's ChemDraw 13.0.

EXAMPLE 1 N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide

Step 1

Optimization of Reaction Conditions

General Procedure:

Dopamine hydrochloride is suspended in ethyl formate at 25-30° C. Thesuspension is cooled to 10-15° C. and sodium tert-butoxide is addedportionwise maintaining the same temperature. The reaction mixture iswarmed to 50-55° C. for 12 hours. After completion of the reaction,ethanol is added to the reaction mass and the temperature is maintainedfor 2 hours. The reaction mass is filtered and washed with 2 volumes ofethanol. The filtrate is concentrated under vacuum and water (0.5volumes) is added to the residue and stirred for 1 hour at 25-30° C. Thesolid is filtered and washed with water (0.25 volumes) and dried in anhot air oven at 55-60° C. for 8 hours.

TABLE 1 Optimization of reaction conditions by varying equivalents ofsodium tert-butoxide Exp. Batch Product Product HPLC No. Size ReactionConditions Quantity Yield Purity 1 250 g Ethyl formate (10 eq) 151 g 63%98.2% Sodium tert-butoxide (2 eq) Ethanol (5 vol) 50-55° C., 12 hours 2250 g Ethyl formate (10 eq) 175 g 73% 92.7% Sodium tert-butoxide (1.6eq) Ethanol (5 vol) 50-55° C., 12 hours 3  50 g Ethyl formate (10 eq)18.5 g 38% 96.8% Sodium tert-butoxide (1.3 eq) Ethanol (5 vol) 50-55°C., 12 hours 4  50 g Ethyl formate (10 eq) 32.6 g 68% 94.4% Sodiumtert-butoxide (1.8 eq) Ethanol (5 vol) 50-55° C., 12 hours

Representative Example—Step 1N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide

Dopamine hydrochloride (250.0 g, 1.323 mol, 1.0 eq) was suspended inethyl formate (2.5 L, 10.0 vol) at 25-30° C. The suspension was cooledto 10-15° C. and sodium tert-butoxide (202 g, 2.12 mol, 1.60 eq) wasadded portionwise maintaining the same temperature. The reaction mixturewas warmed to 55-60° C. for 12 hours and then concentrated under reducedpressure. To the remaining residue, water (125 mL, 0.5 vol) was addedand stirred for 15 minutes. The volatile organic solvents were distilledunder vacuum whereupon the product precipitated. The suspension wascooled to 25-30° C. and purified water (500 mL, 2.0 vol) was added. Thesolid was filtered and washed with water (125 mL, 0.5 vol) and dried inan oven at 55-60° C. for 8 hours to afford the title compound as a brownpowder (203 g, yield=84.5%). ¹H NMR (300 MHz, CDCl₃), δ 8.72 (s, broad,2H), 7.96 (s, 1H), 6.548-6.630 (dd, 2H, J=8.1), 6.407-6.441 (d, 1H,J=2.1), 3.169-3.237 (q, 2H, J=6.9), 2.485-2.535 (t, 2H, J=7.8); LC-MS:m/z=181.92 (MH)⁺.

EXAMPLE 2 d₆-6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride

Step 1

Optimization of Reaction Conditions

General Procedure:

N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide is charged with solvent,base, phase transfer catalyst if any, and d₃-methyl iodide (CD₃I) at25-30° C. The reaction temperature is set and maintained for thespecified time. The reaction is filtered, the filtrate distilled underreduced pressure, and the crude product partitioned betweendichloromethane (6.0 vol) and water (4.0 vol). The layers are separatedand the organic layer is washed twice with 3% aqueous NaOH solution(2×4.0 vol) followed by water (4.0 vol). The organic layer is distilledunder reduced pressure to give cruded₆-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide.

TABLE 2 Optimization of reaction conditions by varying solvent Exp.Batch Product Product HPLC No. Size Reaction Conditions Quantity YieldPurity 1 50 g K₂CO₃ (3 eq) 50 g 86.6% 93.9% CH₃I (2.2 eq) Acetone (8vol) Tetrabutylammonium bromide (0.05 eq) 38-42° C., 36 hours 2 25 gK₂CO₃ (3 eq) 21 g   75% — CH₃I (2.2 eq) Acetonitrile (8 vol)Tetrabutylammonium bromide (0.05 eq) 38-42° C., 36 hours 3 50 g K₂CO₃ (3eq) Not — — CH₃I (2.2 eq) isolated 2-Methyl-tetrahdrofuran (8 vol)Tetrabutylammonium bromide (0.05 eq) 38-42° C., 36 hours

TABLE 3 Optimization of reaction conditions by varying solvent volumeExp. Batch Product Product HPLC No. Size Reaction Conditions QuantityYield Purity 1  20 g K₂CO₃ (3 eq)  22 g  95.3% — CH₃I (3 eq) Acetone (6vol) 18-crown-6 (0.05 eq) 38-42° C., 12 hours 2 100 g K₂CO₃ (3 eq) 116 g~100% 92.4% CH₃I (3 eq) Acetone (8 vol) 18-crown-6 (0.05 eq) 38-42° C.,12 hours

TABLE 4 Optimization of reaction conditions by varying molar equivalentsof methyl iodide Exp. Batch Product Product HPLC No. Size ReactionConditions Quantity Yield Purity 1 50 g K₂CO₃ (3 eq) 44.3 g 76.7% 94.2%CH₃I (2.2 eq) Acetone (8 vol) 28-35° C., 36 hours 2 50 g K₂CO₃ (3 eq)47.6 g 82.4% 90.9% CH₃I (2.4 eq) Acetone (8 vol) 28-35° C., 36 hours 350 g K₂CO₃ (3 eq)   48 g 83.0% 93.5% CH₃I (2.6 eq) Acetone (8 vol)28-35° C., 36 hours

TABLE 5 Optimization of reaction conditions by varying reactiontemperature Exp. Batch Product Product HPLC No. Size Reaction ConditionsQuantity Yield Purity 1 200 g K₂CO₃ (3 eq) 198.9 g 83.7% 93.1% CD₃I (2.2eq) Acetone (8 vol) 28-35° C., 36 hours 2  25 g K₂CO₃ (3 eq)   21 g72.9% 95.8% CH₃I (2.2 eq) Acetone (8 vol) 38-40° C., 36 hours

TABLE 6 Optimization of reaction conditions by varying phase transfercatalyst and methyl iodide equivalents Phase Exp. Batch Transfer CH₃IBase Solvent/ No. Size Catalyst (eq) (eq) (eq) Conditions Result 1 10 gTetrabutyl 3 K₂CO₃ Acetone Worked well ammonium (3.0) 35-45° C., bromide45 hours (0.05) 2 10 g Tetrabutyl 3 K₂CO₃ Acetone Worked well ammonium(3.0) 35-45° C., bromide 45 hours (0.08) 3 10 g None 2.2 Cs₂CO₃ Acetone1.5% (2.0) 35-45° C., Formanide 20 hours methylation, 5% mono-methylated phenol remaining 4 10 g None 2.5 Cs₂CO₃ Acetone 2% Formanide(2.0) 35-45° C., methylation, 20 hours 3% mono- methylated phenolremaining 5 10 g Tetrabutyl 2.2 K₂CO₃ Acetone Worked well ammonium (3.0)35-45° C., bromide 20 hours (0.05) 6 10 g Tetrabutyl 2.5 K₂CO₃ AcetoneWorked well ammonium (3.0) 35-45° C., bromide 20 hours (0.05)

TABLE 7 Optimization of reaction conditions by varying phase transfercatalyst Exp. Batch Product Product HPLC No. Size Reaction ConditionsQuantity Yield Purity 1 30 g K₂CO₃ (3 eq) 28 g 82.3% — CH₃I (2.2 eq)Acetone (8 vol) Tetrabutylammonium bromide (0.05) 38-42° C., 36 hours 225 g K₂CO₃ (3 eq) 24 g   81% — CH₃I (2.2 eq) Acetone (8 vol) 18-Crown-6(0.1) 38-42° C., 36 hours 3 25 g K₂CO₃ (3 eq) 23 g 79.8% 83.4% CH₃I (2.2eq) Acetone (8 vol) Tetrabutylammonium iodide (0.05) 38-42° C., 36 hours

TABLE 8 Optimization of reaction conditions by varying phase transfercatalyst quantity Exp. Batch Product Product HPLC No. Size ReactionConditions Quantity Yield Purity 1 50 g K₂CO₃ (3 eq) 50 g 86.6%  93.9%CH₃I (2.2 eq) Acetone (8 vol) Tetrabutylammonium bromide (0.05) 38-42°C., 36 hours 2 25 g K₂CO₃ (3 eq) 22 g 76.3% 90.78% CH₃I (2.2 eq) Acetone(8 vol) Tetrabutylammonium bromide (0.01) 38-42° C., 36 hours 3 25 gK₂CO₃ (3 eq) 21 g 72.9% 95.85% CH₃I (2.2 eq) Acetone (8 vol) Withouttetrabutylammonium bromide 38-42° C., 36 hours

Representative Example—Step 1d₆-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide

N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide (190 g, 1.049 mol, 1.00 eq)was charged with acetone (1.52 L, 8.0 vol), followed by K₂CO₃ (434 g,3.149 mol, 3.00 eq) at 25-30° C. CD₃I (334 g, 2.309 mol, 2.20 eq) wasadded to the reaction mixture over 1 hour at 25-30° C. The reactiontemperature was maintained for 36 hours at 25-35° C. The reaction wasfiltered, the filtrate was distilled under reduced pressure, and thecrude product was partitioned between dichloromethane (1.14 L, 6.0 vol)and water (760 mL, 4.0 vol). The layers were separated and the organiclayer was washed twice with 3% aqueous NaOH solution (2×760 mL, 2×4.0vol) followed by water (760 mL, 4.0 vol). The organic layer wasdistilled under reduced pressure to give 158 g cruded₆-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide.

Step 2

Optimization of Reaction Conditions

General Procedure:

N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide is charged with solvent andPOCl₃ at 10-15° C. The mixture is heated to an elevated temperature for1 or 2 hours and then is cooled to ambient temperature, after which aquenching solvent (for example, a protic solvent such as an alcohol) isadded and the mixture is stirred for 1 hour followed by addition of ananti-solvent if applicable. In some cases,d₆-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride precipitates inthe form of a salt directly from the reaction mixture. In others,d₆-6,7-dimethoxy-3,4-dihydroisoquinoline is isolated after acid-baseworkup.

TABLE 9 Optimization of reaction conditions by varying the solvent Exp.Batch Reaction Quenching/ Product Product HPLC No. Size ConditionsAnti-Solvent Quantity Yield Purity 1 93 g POCl₃ (1 eq) None  49 g 57.6%90.0% Acetonitrile (10 vol) 80-85° C., 2 hours 2 200 g  POCl₃ (1 eq)None 112 g 61.5% 84.6% Toluene (2 vol) 90-95° C., 1 hours 3 20 g POCl₃(1 eq) None sticky — — MTBE* (4 vol) mass 0-30° C. 4 20 g POCl₃ (1 eq)None sticky — — DCM* (2 vol) mass 0-30° C. *DCM = Dichloromethane; MTBE= Methyl tert-butyl ether.

TABLE 10 Optimization of reaction conditions by varying quenchingsolvent and anti-solvent (reaction solvent toluene) Exp. Batch ReactionQuenching/ Product HPLC No. Size Conditions Anti-Solvent Quantity YieldPurity 1 48 g POCl₃ (1.8 eq) Ethanol (3.8 eq) Product not — — Toluene (2vol) MTBE* (4 vol) obtained as 90-95° C., 1 hour a free solid 2 48 gPOCl₃ (distilled, Ethanol (3.8 eq) 20.2 g  46% 91.9% 1.8 eq) MTBE* (4vol) Toluene (2 vol) 90-95° C., 1 hour 3 50 g POCl₃ (1 eq) Ethyl Acetate(2  35 g  76% — Toluene (2 vol) vol) 90-95° C., 1 hour Ethyl Acetate/HCl (2 vol) 4 20 g POCl₃ (distilled, Ethanol (2.4 eq) Product not — —1.8 eq) MTBE* (4 vol) obtained as Toluene (2 vol) a free solid 40-45°C., 1 hour 5 50 g POCl₃ (distilled, Ethanol (3.8 eq) Product not — — 1.8eq) MTBE* (4 vol) obtained as Toluene (2 vol) 80-85° C., 1 hour, a freesolid seeded with product 6 28 g POCl₃ (1.8 eq) Ethanol (3.8 eq)  24g >100%  Isolated Toluene (2 vol) MTBE* (4 vol) by acid- 90-95° C., 2hours base workup 7 25 g POCl₃ (1.8 eq) IPA* (3.8 eq) 14.5 g 53.2% 80.2%Toluene (2 vol) MTBE* (4 vol) (black 90-95° C., 2 hours 12 hours solid)8 25 g POCl₃ (1.8 eq) 1-Butanol (3.8 20.1 g 73.5% 80.1% Toluene (2 vol)eq) (black 90-95° C., 2 hours MTBE* (4 vol) solid) 12 hours 9 25 g POCl₃(1.8 eq) 1-Propanol (3.8 Product not — — Toluene (2 vol) eq) obtained as90-95° C., 2 hours Cyclohexane (4 a free solid vol) 12 hours *IPA =Isopropyl alcohol; MTBE = Methyl tert-butyl ether.

TABLE 11 Optimization of reaction conditions by varying quenchingsolvent and anti-solvent (reaction solvent acetonitrile) Exp. BatchReaction Quenching/ Product HPLC No. Size Conditions Anti-SolventQuantity Yield Purity 1 100 g  POCl₃ (1.8 eq) Ethanol (3.8 eq)  110 g —93.3% Acetonitrile (2 vol) MTBE* (4 vol) (hygroscopic) 80-85° C., 1 hour12 hours, seededwith product 2 25 g POCl₃ (1.8 eq) IPA* (3.8 eq)  17 g62.4% 87.1% Acetonitrile (2 vol) MTBE* (4 vol) (black 80-85° C., 2 hours12 hours, solid) 3 25 g POCl₃ (1.8 eq) 1-Butanol (3.8 17.3 g 63.8% 95.6%Acetonitrile (2 vol) eq) (grey 80-85° C., 2 hours MTBE* (4 vol) solid)12 hours 5 25 g POCl₃ (1.8 eq) t-Butanol (3.8 Solid not — — Acetonitrile(2 vol) eq) isolated 80-85° C., 2 hours MTBE* (4 vol) 12 hours 6 25 gPOCl₃ (1.8 eq) 1-Propanol (3.8  17 g 62.4% 88.8% Acetonitrile (2 vol)eq) (gray 80-85° C., 2 hours MTBE* (4 vol) solid) 12 hours 7 25 g POCl₃(1.8 eq) 1-Pentanol (3.8 13.4 g 49.2% Brown Acetonitrile (2 vol) eq)solid 80-85° C., 2 hours MTBE* (4 vol) 12 hours 8 25 g POCl₃ (1.8 eq)2-methyl 12.77 g  46.9% 87.6% Acetonitrile (2 vol) propanol (3.8 eq)(gray 80-85° C., 2 hours MTBE* (4 vol) solid) 12 hours *IPA = Isopropylalcohol; MTBE = Methyl tert-butyl ether.

TABLE 12 Optimization of reaction conditions by varying anti-solvent(reaction solvent acetonitrile, 1-butanol as a quenching solvent) Exp.Batch Reaction Quenching/ Product Product HPLC No. Size ConditionsAnti-Solvent Quantity Yield Purity 1 25 g POCl₃ (1.8 eq) 1-butanol (3.8eq) 13.3 g 48.8% 91.9% Acetonitrile (2 Ethyl acetate vol) (4 vol) 80-85°C., 2 hours 12 hours 2 25 g POCl₃ (1.8 eq) 1-butanol (3.8 eq) 14.83 g 54.5% 94.4% Acetonitrile (2 Isopropyl acetate vol) (4 vol) 80-85° C., 2hours 12 hours 3 25 g POCl₃ (1.8 eq) 1-butanol (3.8 eq) 14.2 g 52.2%93.3% Acetonitrile (2 2-methyl-THF* vol) (4 vol) 80-85° C., 2 hours 12hours 4 25 g POCl₃ (1.8 eq) 1-butanol (3.8 eq) 13.0 g 47.7% 94.2%Acetonitrile (2 Ethyl acetate/ vol) HCl (4 vol) 80-85° C., 2 hours 12hours 5 25 g POCl₃ (1.8 eq) 1-butanol (3.8 eq) 18.3 g 67.2% 93.5%Acetonitrile (2 MTBE* (4 vol) vol) 12 hours 80-85° C., 2 hours 6 25 gPOCl₃ (1.8 eq) 1-butanol (3.8 eq) 17.5 g 64.3% 91.3% Acetonitrile (2MTBE* (8 vol) vol) 12 hours 80-85° C., 2 hours *MTBE = Methyl tert-butylether; 2-methyl-THF = 2-methyltetrahydrofuran (4 vol).

TABLE 13 Optimization of reaction conditions by varying equivalents of1-butanol (reaction solvent acetonitrile, 1-butanol as a quenchingsolvent) Exp. Batch Reaction Quenching/ Product Product HPLC No. SizeConditions Anti-Solvent Quantity Yield Purity 1 25 g POCl₃ (1.8 eq)1-butanol (6.0 eq) 14.7 g 54% 84.1% Acetonitrile (2 MTBE* (4 vol) vol)12 hours 80-85° C., 2 hours 2 28 g POCl₃ (1.8 eq) 1-butanol (3.8 eq)21.3 g 70% 94.6% Acetonitrile (2 MTBE* (4 vol) vol) 12 hours 80-85° C.,2 hours *MTBE = Methyl tert-butyl ether;

TABLE 14 Optimization of reaction conditions by using methyl tert-butylether as reaction solvent and varying the quenching solvent Exp. BatchReaction Quenching/ Product Product HPLC No. Size ConditionsAnti-Solvent Quantity Yield Purity 1 25 g POCl₃ (1.8 eq) Ethanol (3.8eq) Solid not — — MTBE* (4 vol) 12 hours isolated 55-60° C., 2 hours 225 g POCl₃ (1.8 eq) 1-butanol (3.8 eq) 10.5 g 38.5% 74.4% MTBE* (4 vol)12 hours (brown 45-50° C., 2 hours solid) *MTBE = Methyl tert-butylether;

TABLE 15 Optimization of reaction conditions by varying the equivalentsof POCl₃ used Exp. Batch Reaction Quenching/ Product Product HPLC No.Size Conditions Anti-Solvent Quantity Yield Purity 1 50 g POCl₃ (0.5 eq)1-butanol (3.8 eq) — — Product Acetonitrile (2 MTBE* (4 vol) obtainedvol) 12 hours as a 80-85° C., 2 hours gummy solid 2 50 g POCl₃ (1.0 eq)1-butanol (3.8 eq) — — Product Acetonitrile (2 MTBE* (4 vol) obtainedvol) 12 hours as a 80-85° C., 2 hours gummy solid 3 25 g POCl₃ (1.8 eq)1-butanol (3.8 eq) 17.3 g 63.8% 98.6% Acetonitrile (2 MTBE* (4 vol) vol)12 hours 80-85° C., 2 hours

Representative Example—Step 2 d₆-6,7-Dimethoxy-3,4-dihydroisoquinolinehydrochloride

To the crude d₆-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide from step1, (158 g, 0.734 mol, 1.00 eq), acetonitrile (316 mL, 2.0 vol) was addedfollowed by POCl₃ (202 g, 1.322 mol, 1.80 eq) at 10-15° C. The reactionmixture was heated to reflux for 2 hours and then cooled to 25-35° C.The temperature was maintained for 12 hours after which it was quenchedwith n-butanol (255 mL, 2.79 mol, 3.8 eq) and methyl tert-butyl ether(1.26 L, 8.0 vol). The precipitated product was filtered, washed withethyl acetate (632 mL, 4.0 vol), and dried under vacuum. The crudeproduct was further purified by slurrying in 10% Ethanol in MTBE (944mL, 8.0 vol) whereupon an orange brown product (108 g, yield=44.0%) wasobtained after drying. ¹H NMR (300 MHz, CDCl₃), δ 14.456 (br s, 1H),9.105-9.133 (d, 1H, J=8.4), 7.497 (s, 1H), 6.806 (s, 1H), 3.951-4.000(t, 2H, J=7.5), 3.089-3.144 (t, 2H, J=8.4); LC-MS: m/z=198.06 (MH)⁺.

Step 3—Optional purification of d₆-6,7-dimethoxy-3,4-dihydroisoquinolinehydrochloride

To increase the purity of d₆-6,7-dimethoxy-3,4-dihydroisoquinolinehydrochloride various purification procedures were attempted.

TABLE 16 Recrystallization of d₆-6,7-dimethoxy- 3,4-dihydroisoquinolinehydrochloride Exp. Batch Product Product HPLC No. Size ReactionConditions Quantity Yield Purity 1 5 g 6,7-Dimethoxy-3,4-  2.1 g   42%94.5% dihydroisoquinoline hydrochloride (1 eq) Ethanol (3 vol) 60-65°C., 1 hour Cooled and filtered at 25-30° C. 2 5 g 6,7-Dimethoxy-3,4- 1.4 g 28.0% 89.0% dihydroisoquinoline hydrochloride (1 eq) Ethanol (8vol) 75-80° C., 16 hours Cooled and filtered at 25-30° C. 3 5 g6,7-Dimethoxy-3,4- 1.02 g 20.4% 84.8% dihydroisoquinoline hydrochloride(1 eq) 1-Propanol (8 vol) 95-100° C., 16 hours Cooled and filtered at25-30° C. 4 5 g 6,7-Dimethoxy-3,4- 0.85 g 17.0% 76.0%dihydroisoquinoline hydrochloride (1 eq) 1-Butanol (8 vol) 115-120° C.,16 hours Cooled and filtered at 25-30° C. 5 5 g 6,7-Dimethoxy-3,4- 1.19g 23.8% 85.7% dihydroisoquinoline hydrochloride (1 eq) 1-Pentanol (8vol) 135-140° C., 16 hours Cooled and filtered at 25-30° C.

TABLE 17 Reslurry and washing of d₆-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride Exp. Batch Product Product HPLCNo. Size Reaction Conditions Quantity Yield Purity 1 2 g6,7-Dimethoxy-3,4- 1.75 g 83.3% 93.3% dihydroisoquinoline hydrochloride(1 eq) Acetone (3 vol) Stirred at 25-30° C. for 2 hours, then filteredand dried 2 2 g 6,7-Dimethoxy-3,4- 1.21 g   60% 94.5%dihydroisoquinoline hydrochloride (1 eq) Acetonitrile (2 vol) Stirred at25-30° C. for 2 hours, then filtered and dried 3 2 g 6,7-Dimethoxy-3,4-1.35 g 67.5% — dihydroisoquinoline hydrochloride (1 eq)Ethanol/acetonitrile/ acetone (1:1:8) (3 vol) Stirred at 25-30° C. for 2hours, then filtered and dried 4 2 g 6,7-Dimethoxy-3,4- 1.78 g   89% —dihydroisoquinoline hydrochloride (1 eq) Methanol/ethyl acetate (5:95)(3 vol) Stirred at 25-30° C. for 2 hours, then filtered and dried 5 2 g6,7-Dimethoxy-3,4- 1.34 g   67% — dihydroisoquinoline hydrochloride (1eq) Methanol/ethyl acetate (5:95) (3 vol) Stirred at 25-30° C. for 1hour, then filtered and dried 6 2 g 6,7-Dimethoxy-3,4- 1.46 g   73% —dihydroisoquinoline hydrochloride (1 eq) Ethanol/acetone/ethyl acetate(1:1:8) (3 vol) Stirred at 25-30° C. for 1 hour, then filtered and dried7 1 g 6,7-Dimethoxy-3,4- 0.55 g   55% — dihydroisoquinolinehydrochloride (1 eq) Ethanol/ethyl acetate (1:9) (3 vol) Stirred at25-30° C. for 1 hour, then filtered and dried 8 5 g 6,7-Dimethoxy-3,4- 4.8 g 96.0% 93.5% dihydroisoquinoline hydrochloride (1 eq) Ethylacetate (5 vol) Stirred at 28-32° C. for 16 hours, then filtered anddried 9 5 g 6,7-Dimethoxy-3,4- 4.87 g 97.4% 79.1% dihydroisoquinolinehydrochloride (1 eq) Methyl tert-butyl ether (5 vol) Stirred at 28-32°C. for 16 hours, then filtered and dried 10 5 g 6,7-Dimethoxy-3,4- 4.31g 86.2% 94.1% dihydroisoquinoline hydrochloride (1 eq) Acetone (3 vol)Stirred at 28-32° C. for 16 hours, then filtered and dried 11 5 g6,7-Dimethoxy-3,4- 1.63 g 32.6% 90.9% dihydroisoquinoline hydrochloride(1 eq) Acetonitrile (3 vol) Stirred at 28-32° C. for 16 hours, thenfiltered and dried 12 5 g 6,7-Dimethoxy-3,4-  3.4 g   68% 91.7%dihydroisoquinoline hydrochloride (1 eq) Methyl tert-butyl ether (6 vol)50-55° C. 1-butanol (12 vol) Stirred at 28-32° C. for 16 hours, thenfiltered and dried 13 5 g 6,7-Dimethoxy-3,4-  4.3 g   86% 87.6%dihydroisoquinoline hydrochloride (1 eq) Methyl tert-butyl ether/ethanol (9:1) (6 vol) Stirred at 28-32° C. for 16 hours, then filteredand dried 14 150 g  6,7-Dimethoxy-3,4-  138 g   92% 99.0%dihydroisoquinoline hydrochloride (1 eq) Methyl tert-butyl ether/ethanol (9:1) (6 vol) Stirred at 28-32° C. for 16 hours, then filteredand dried

EXAMPLE 3(RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one((+/−)-d₆-Tetrabenazine)

Step 1

Representative Example—Step 12-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide

3-[(dimethylamino)methyl]-5-methyl-hexan-2-one (90 g, 0.526 mol, 1.00eq) was charged with methyl tert-butyl ether (1.35 L, 15.0 vol) andcooled 0-10° C. Methyl iodide (171 g, 1.209 mol, 2.3 eq) was addedslowly to the reaction mixture and stirred for 15 hours at 25-35° C. Thereaction was warmed to 35-40° C. for 2 hours. The precipitated solid wasfiltered under nitrogen and was washed with methyl tert-butyl ether (900mL, 10.0 vol). The crude product was further purified by slurrying inethyl acetate (1.46 L, 10 vol) and filtered to give2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (146 g) as a whitesolid.

Step 2

Optimization of Reaction Conditions

General Procedure:

2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide is charged to asuspension containing d₆-6,7-dimethoxy-3, 4-dihydroisoquinoline(hydrochloride or freebase, 1.00 eq) and solvent. If d₆-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride is used, a base is added to thereaction mixture at room temperature. The reaction mixture is stirred atthe appropriate temperature, cooled, and water is added. The reactionmass is filtered and the solids are washed with water and dried toafford the title compound [The (RR, SS)-diastereomer of d₆-tetrabenazineis the desired product].

TABLE 18 Optimization of the reaction by varying the solvent Exp. BatchProduct HPLC No. Size Reaction Conditions Quantity Product Yield Purity1 30 g 6,7-Dimethoxy-3,4-dihydro 20.3 g  40.7% 98.8% isoquinoline freebase (1 eq) 0.56% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereomerpentanaminium iodide (0.75 eq) impurity* Water (6 vol) 100° C., 48 hour2 10 g 6,7-Dimethoxy-3,4-dihydro 1.4 g  8.3% 97.8% isoquinoline freebase (1 eq) 1.45% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereomerpentanaminium iodide (0.75 eq) impurity* Methanol (6 vol) 65-70° C., 48hour 3 10 g 6,7-Dimethoxy-3,4-dihydro 1.4 g  8.3% 98.1% isoquinolinefree base (1 eq) 0.75% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereomerpentanaminium iodide (0.75 eq) impurity* Ethanol (6 vol) 75-80° C., 48hour 4 10 g 6,7-Dimethoxy-3,4-dihydro 6.8 g 40.8% 99.1% isoquinolinefree base (1 eq) 0.04% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereomerpentanaminium iodide (0.75 eq) impurity* Methanol/water (1:1) (6 vol)45-50° C., 90 hour *The diastereomer impurity is the (RS, SR)diastereomer of d₆-tetrabenazine.Tables 19 and 20—In-process HPLC results

Ex. 2 Methanol Ex. 3 - Ethanol Diaste- Diaste- Time SM* Product reomer*SM* Product reomer*  6 h 17.2% 12.5% 2.6% 3.3% 12.4% 3.0% 18 h 4.3%17.1% 3.8% 0.2% 14.6% 3.9% 24 h 1.2% 16.8% 4.5% 0.1% 17.2% 5.2% 30 h0.5% 14.0% 3.2% 0.3% 12.4% 3.3% 42 h 0.3% 12.3% 3.1% 0.2% 9.6% 2.6% 48 h0.3% 12.1% 2.9% 0.2% 12.0% 2.9% Product — 97.8% 1.4% — 98.1% 0.75% Wt(g)  1.38 Wt (g)  1.38 Y (%) 8.3 Y (%) 8.3 *SM = Starting material -[6,7-Dimethoxy-3,4-dihydro isoquinoline]; The diastereomer impurity isthe (RS,SR) diastereomer of d₆-tetrabenazine.

Ex. 4 - Methanol:Water (1:1) Time SM* Product Diastereomer*  6 h — — —18 h 3.1%  21.% 0.7% 24 h — — — 30 h — — — 42 h 1.8% 23.9% 0.5% 48 h — —— 90 h — 28.1% 1.0% Product — 99.1% 0.04%  Wt (g) 6.78 g Y (%) 40.8 *SM= Starting material - [6,7-Dimethoxy-3,4-dihydro isoquinoline]; Thediastereomer impurity is the (RS, SR) diastereomer of d₆-tetrabenazine.

TABLE 21 Optimization of the reaction by varying the reactiontemperature Exp. Batch Product HPLC No. Size Reaction ConditionsQuantity Product Yield Purity 1 8 g 6,7-Dimethoxy-3,4-dihydroiso- 8.3 g74.5% 99.1% quinoline hydrochloride (1 eq) 0.04%2-acetyl-N,N,N,4-tetramethyl-1- Diastereomer pentanaminium iodide (1.08eq) impurity* Methanol/water (1:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 63hour 2 8 g 6,7-Dimethoxy-3,4-dihydroiso- 8.5 g 76.7% 99.1% quinolinehydrochloride (1 eq) 0.04% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereomerpentanaminium iodide (1.08 eq) impurity* Methanol/water (1:1) (6 vol)K₂CO₃ (1 eq) 25-30° C., 63 hour 3 8 g 6,7-Dimethoxy-3,4-dihydroiso- 8.3g   75% 99.1% quinoline hydrochloride (1 eq) 0.1%2-acetyl-N,N,N,4-tetramethyl-1- Diastereomer pentanaminium iodide (1.08eq) impurity* Methanol/water (1:1) (6 vol) K₂CO₃ (1 eq) 65-70° C., 63hour *The diastereomer impurity is the (RS, SR) diastereomer ofd₆-tetrabenazine.Tables 22 and 23—In-process HPLC results

Ex. 3 - Methanol:Water Ex. 2 - Methanol:Water (1:1) 65-70° C. (1:1)45-50° C. Diaste- Diaste- Hours SM* Product reomer* SM* Product reomer*15 h 0.8% 8.1% 0.5% — 23.5% 0.1% 23 h — 33.1% 0.5% — 17.1% 0.2% 39 h —14.3% 0.4% — 22.0% 0.1% 47 h — 17.9% 0.5% — 35.9% 0.3% 63 h — 44.4% 0.8%— 58.2% 0.4% Crude — 88.6% 1.8% — 92.3% 0.6% After EA — 91.6% 1.3% —95.2% 0.6% Final — 99.19% 0.1% — 99.15% 0.04% Product Wt (g)  8.38 Wt(g)  8.32 Y (%) 75 Y (%) 74.5 *SM = Starting material -[6,7-Dimethoxy-3,4-dihydro isoquinoline]; The diastereomer impurity isthe (RS,SR) diastereomer of d₆-tetrabenazine.

Ex. 1 - Methanol:Water (1:1) 25-30° C. Hours SM* Product Diastereomer*15 h — 31.6% 0.2% 23 h — 29.5% 0.2% 39 h — 35.2% 0.2% 47 h — 20.9% 0.1%63 h — 63.4% 0.3% Crude — 95.7% 0.5% After — 95.5% 0.4% EA* treatmentFinal — 99.16%  0.04%  Product Wt (g)  8.56 Y (%) 76.7 *SM = Startingmaterial - [6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl Acetate;The diastereomer impurity is the (RS, SR) diastereomer ofd₆-tetrabenazine.

TABLE 24 Optimization of the reaction by varying the solvent mixtureratio Exp. Batch Product No. Size Reaction Conditions Quantity ProductYield HPLC Purity 1  8 g 6,7-Dimethoxy-3,4-dihydroiso- 8.5 g 76.9% 98.9%quinoline hydrochloride (1 eq) 0.09% 2-acetyl-N,N,N,4-tetramethyl-1-undesired pentanaminium iodide (1.08 eq) isomer Methanol/water (1:3) (6vol) K₂CO₃ (1 eq) 45-50° C., 63 hour 2  8 g6,7-Dimethoxy-3,4-dihydroiso- 8.6 g 77.1% 99.6% quinoline hydrochloride(1 eq) 0.03% 2-acetyl-N,N,N,4-tetramethyl-1- undesired pentanaminiumiodide (1.08 eq) isomer Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50°C., 63 hour 3 10 g 6,7-Dimethoxy-3,4-dihydroiso- 9.6 g 68.9% 99.3%quinoline hydrochloride (1 eq) off-white 2-acetyl-N,N,N,4-tetramethyl-1-product pentanaminium iodide (1.08 eq) Methanol/water (4:1) (6 vol)K₂CO₃ (1 eq) 45-50° C., 63 hour 4 10 g 6,7-Dimethoxy-3,4-dihydroiso- 7.6g 54.4% 99.2% quinoline hydrochloride (1 eq)2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol(6 vol) K₂CO₃ (1 eq) 45-50° C., 63 hourTables 25 and 26—In-process HPLC results

Ex. 1 - Methanol:Water Ex. 2 - Methanol:Water (1:3) 45-50° C. (3:1)45-50° C. Diaste- Diaste- Hours SM* Product reomer* SM* Product reomer*24 h — 44.7% 0.4% — 18.6% 0.5% 48 h — 54.8% 0.6% — 18.9% 0.5% 63 h —70.0% 0.8% — 16.0% 0.8% Crude — 91.1% 1.3% — 98.5% 0.4% After EA* —92.6% 1.0% — 98.7% 0.4% treatment Final — 98.98% 0.09% — 99.64% 0.03%Product Wt (g)  8.59 8.61 Y (%) 76.9 77.1 *SM = Starting material -[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl Acetate; Thediastereomer impurity is the (RS,SR) diastereomer of d₆-tetrabenazine.

Ex. 3 - Methanol:Water Ex. 4 - Methanol, (4:1) 45-50° C. 45-50° C.Diaste- Diaste- Hours SM* Product reomer* SM* Product reomer* 24 h — — —— — — 48 h — — — — — — 63 h — 17.75% 2.57% — 17.75% 2.57% Crude — 97.97%0.59% — 97.97% 0.59% After EA* — 98.15% 0.35% — 98.15% 0.35% treatmentFinal — 99.28% 0.03% — 99.28% 0.03% Product 7.58 7.58 54.4 54.4 *SM =Starting material - [6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = EthylAcetate; The diastereomer impurity is the (RS,SR) diastereomer ofd₆-tetrabenazine.

TABLE 27 Optimization of the reaction by varying the reaction time Exp.Batch Product No. Size Reaction Conditions Quantity Product Yield HPLCPurity 1 10 g 6,7-Dimethoxy-3,4-dihydroiso- 8.5 g 61% 99.2% quinolinehydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminiumiodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 24hour 2 10 g 6,7-Dimethoxy-3,4-dihydroiso- 9.4 g 67.4%   99.5% quinolinehydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminiumiodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 48hour 3 10 g 6,7-Dimethoxy-3,4-dihydroiso- 9.2 g 66% 99.2% quinolinehydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminiumiodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 63hourTables 28 and 29—In-process HPLC results

Ex. 1 - Methanol:Water Ex. 2 - Methanol:Water (3:1) 45-50° C., 24 h(3:1) 45° C., 48 h Diaste- Diaste- Hours SM* Product reomer* SM* Productreomer* 24 h 1.52% 15.65% 1.38% — — — 48 h — — — — 23.73% 0.66% 63 h — —— — — — Crude — 92.1% 1.96% — 91.83% 1.53% After EA* — 91.96% 1.17% —91.64% 1.57% treatment Final — 99.25% 0.08% — 99.58% 0.03% Product Wt(g)  8.5 Wt (g)  9.4 Y (%) 61 Y (%) 67.4 *SM = Starting material -[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl Acetate; Thediastereomer impurity is the (RS,SR) diastereomer of d₆-tetrabenazine.

Ex. 3 - Methanol:Water (3:1) 45° C., 63 h Hours SM* ProductDiastereomer* 24 h — — — 48 h — — — 63 h — 13.63% 0.71% Crude — 98.43%0.34% After — 98.24% 0.45% EA* treatment Final — 99.29% 0.04% Product Wt(g)  9.2 Y (%) 66.0 *SM = Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; EA = Ethyl Acetate; The diastereomer impurity is the (RS,SR) diastereomer of d₆-tetrabenazine.

TABLE 30 Comparison of d₀-6,7-dimethoxy-3,4-dihydroiso-quinolinehydrochloride and d₆-6,7-dimethoxy-3,4-dihydroiso-quinolinehydrochloride Exp. Batch Product No. Size Reaction Conditions QuantityProduct Yield HPLC Purity 1 10 g d₀-6,7-Dimethoxy-3,4-dihydro 9.4 g67.4% 99.5% isoquinoline hydrochloride (1 eq)2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq)Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 48 hours 2 10 gd₆-6,7-Dimethoxy-3,4-dihydro 9.96 g  72.0% 99.9% isoquinolinehydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminiumiodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 48hours 3 10 g d₆-6,7-Dimethoxy-3,4-dihydro 9.4 g 68.3% 99.8% isoquinolinehydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminiumiodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 48hours 4 125 g  d₆-6,7-Dimethoxy-3,4-dihydro 125.7 g  72.77% 99.64%isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq)45-50° C., 48 hours

TABLE 31 Optimization by varying the purity of 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride Batch Exp. Size Product No. (Purity) ReactionConditions Quantity Product Yield HPLC Purity 1 10 g6,7-Dimethoxy-3,4-dihydro  9.2 g   66% 99.5% (87.1%) isoquinolinehydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminiumiodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 63hours 2  8 g 6,7-Dimethoxy-3,4-dihydro 8.61 g 77.1% 99.9% (90.3%)isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq)45-50° C., 63 hours 3  4 g 6,7-Dimethoxy-3,4-dihydro 4.72 g 84.7% 99.8%(99.0%) isoquinoline hydrochloride (1 eq)2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq)Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 63 hours 4 50 g6,7-Dimethoxy-3,4-dihydro 59.7 g 85.6% 99.64% (99.0%) isoquinolinehydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminiumiodide (1.08 eq) Methanol/water (3:1) (6 vol) K₂CO₃ (1 eq) 45-50° C., 63hours

Representative Example—Step 2(RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

The 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide from step 1 (146g) was charged to a suspension containing d₆-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (90 g, 0.385 mol, 1.00 eq), methanol(405 mL, 4.5 vol) and water (135 mL, 1.5 vol) at 25-30° C. To thereaction mixture K₂CO₃ (54 g, 0.385 mol, 1.00 eq) was added at 25-30° C.and stirred at 40-45° C. for 30 hours. The reaction mixture was cooledand water (270 mL, 3.0 vol) was added. The reaction mass was filteredand the solids were washed with water (270 mL, 3.0 vol) and dried in anoven for 12 hours at 50-55° C. to afford the crude title compound as alight brown powder (100 g, yield=80.6%). ¹H NMR (300 MHz, CDCl₃), δ 6.62(s, 1H), 6.55 (s, 1H), 3.54 (d, 1H, J=11.7), 3.31 (dd, 1H, J=11.4 and6.3), 3.11 (m, 2H), 2.92 (dd, 1H, J=13.5 and 3.3), 2.73 (m, 2H), 2.59(m, 2H), 2.39 (t, 1H, J=11.7), 1.82 (m, 1H), 1.65 (m, 1H), 1.03 (m, 1H),0.90 (m, 6H); LC-MS: m/z=324.18 (MH)⁺.

Step 3—Purification of(RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-oneRepresentative Example

Crude (RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-onefrom step 2 (90 g) was charged into absolute ethanol (540 mL, 6.0 vol)and heated to 75-85° C. for 1 hour. The reaction mass was filteredthrough a Buchner funnel at 75-85° C. and the filter cake was washedwith hot ethanol (45 mL, 0.5 vol). The filtrate was cooled to 25-30° C.over 4 hours and further cooled to 0-5° C. over 3-4 hours. The resultingsolid was filtered, washed with cold ethanol (180 mL, 2.0 vol), anddried under vacuum to afford the title compound as a pale yellowcrystalline powder (75 g, yield=83.3%). ¹H NMR (300 MHz, CDCl₃), δ 6.62(s, 1H), 6.55 (s, 1H), 3.54 (d, 1H, J=11.7), 3.31 (dd, 1H, J=11.4 and6.3), 3.11 (m, 2H), 2.92 (dd, 1H, J=13.5 and 3.3), 2.73 (m, 2H), 2.59(m, 2H), 2.39 (t, 1H, J=11.7), 1.82 (m, 1H), 1.65 (m, 1H), 1.03 (m, 1H),0.90 (m, 6H); LC-MS: m/z=324.18 (MH)⁺.

EXAMPLE 4 3-[(Dimethylamino)methyl]-5-methyl-hexan-2-one

Step 1

2-Acetyl-4-methylpentanoic acid ethyl ester

To a solution of ethyl acetoacetate (500 g, 3.842 mol, 1.00 eq) in DMF(1.5 L, 3.0 vol), KI (63.7 g, 0.384 mol, 0.10 eq), tetrabutylammoniumbromide (136 g, 0.422 mol, 0.11 eq) and K₂CO₃ (632 g, 4.572 mol, 1.19eq) were charged at 25-35° C. The reaction mixture was heated to 40-50°C. and 1-bromo 2-methyl propane (579 g, 4.226 mol, 1.10 eq) was addedover 1 hour. The reaction mixture was heated to 65-75° C. for 6 hours,cooled and quenched with water (5.0 L, 10.0 vol). The reaction mixturewas extracted with toluene (2×2.0 L, 2×4.0 vol) and the combined organiclayers were washed with water (2×1.5 L, 2×3.0 vol). The organic layerwas evaporated under reduced pressure to obtain crude2-acetyl-4-methylpentanoic acid ethyl ester.

Step 2

3-[(Dimethylamino)methyl]-5-methyl-hexan-2-one

The ester was hydrolyzed using potassium hydroxide (212 g, 3.78 mol, 1.1eq) in water (3.84 L, 6.0 vol). After the hydrolysis, the reactionmixture was washed with methyl tert-butyl ether (2×2.56 L, 2×4.0 vol)and the pH of the reaction mixture was adjusted to 6.8-7.2 usingconcentrated HCl (96 mL, 0.15 vol). Dimethylamine hydrochloride solution(420 g, 5.16 mol, 1.50 eq dissolved in 0.224 L, 0.35 vol of purifiedwater), and formaldehyde solution (0.428 L, 5.763 mol, 1.675 eq) andtetrabutylammonium bromide (110 g, 0.344 mol, 0.10 eq) were added to thereaction mixture, and the pH was adjusted to below 1 using concentratedHCl (0.352 L, 0.55 vol) over 1 hour at 25-35° C. The reaction mixturewas stirred for 15 hours at 25-35° C. and the pH was adjusted to12.0-13.0 using 20% aqueous KOH (3.20 L, 5.0 vol) solution at 25-35° C.and dimethylamine hydrochloride (420 g, 5.16 mol, 1.5 eq) was added. Thereaction mixture was stirred for 36 hours at 25-35° C. and the pH of thereaction mixture was adjust to below 1 using concentrated HCl (0.84 L,0.13 vol) at 25-35° C. over 1 h. The reaction mixture was washed withmethyl tert-butyl ether (2×2.56 L, 2×4.0 vol) and the pH of the reactionmixture was adjusted to 9-10 by using 20% aqueous KOH solution (1.72 L,2.68 vol) at 25-35° C. The product was extracted with ethyl acetate(2×2.56 L, 2×4.0 vol and 1×1.28 L, 1×2.0 vol) and the combined organiclayers were washed sequentially with purified water (2×1.92 L, 2×3.0vol) and 10% ammonium chloride solution (2×3.2 L, 2×5.0 vol). Activatedcarbon (32 g, 0.05% w/w) was added to the organic layer and the mixturewas stirred for 30-45 minutes at 25-35° C. The organic layer wasfiltered through celite (106 g) and was washed with ethyl acetate (0.32L, 0.5 vol). The filtrate was distilled under reduced pressure to affordthe title compound as a pale yellow liquid (151 g, yield=22.3%). ¹H NMR(300 MHz, CDCl₃), δ 2.7-2.85 (m, 1H), 2.56-2.6 (m, 1H), 2.16 (s, 7H),2.13 (s, 3H), 1.12-1.55 (m, 3H), 0.92 (d, 3H), 0.89 (d, 3H); LC-MS:m/z=172.11 (MH)⁺.

From the foregoing description, one skilled in the art can ascertain theessential characteristics of this invention, and without departing fromthe spirit and scope thereof, can make various changes and modificationsof the invention to adapt it to various usages and conditions.

What is claimed is:
 1. A process of preparing a racemic mixture of(RR,SS)-d₆-tetrabenazine

(RR, SS)-d₆-tetrabenazine wherein the deuterium enrichment of the (RR,SS)-d₆-tetrabenazine is no less than about 10%, comprising: reactingd₆-6,7-dimethoxy-3,4-dihydroisoquinoline, or a salt thereof:

d₆-6,7-dimethoxy-3,4-dihydroisoquinoline with a salt of2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium:

wherein X is halogen, alkyl sulfate, alkyl sulfonate, halosulfonate,perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate,dialkyloxonium, alkylphosphate, or alkyl carbonate; and an optionalbase; in the presence of a solvent mixture that is a combination ofwater and an alcohol that is methanol or ethanol; for a period of timeand at a temperature sufficient to produce the (RR,SS)-d₆-tetrabenazinehaving a diastereomeric purity of at least 99%, based on highperformance liquid chromatography.
 2. The process of claim 1, whereinthe solvent mixture is a combination of methanol and water.
 3. Theprocess of claim 2, wherein the ratio of methanol:water is about 5:1 toabout 1:1.
 4. The process of claim 2, wherein the ratio ofmethanol:water is about 3:1.
 5. The process of claim 2, wherein theratio of methanol:water is about 1:1.
 6. The process of claim 1, whereinthe solvent mixture is a combination of ethanol and water.
 7. Theprocess of claim 1, wherein the d₆-6,7-dimethoxy-3,4-dihydroisoquinolineis a salt form of d₆-6,7-dimethoxy-3,4-dihydroisoquinoline.
 8. Theprocess of claim 7, wherein the salt form ofd₆-6,7-dimethoxy-3,4-dihydroisoquinoline isd₆-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride.
 9. The processof claim 8, wherein the process is carried out in the presence of abase.
 10. The process of claim 9, wherein the base is K₂CO₃.
 11. Theprocess of claim 1, wherein X is halogen.
 12. The process of claim 11,wherein the halogen is iodide.
 13. The process of claim 1, wherein theperiod of time is about 24 hours to about 63 hours.
 14. The process ofclaim 1, wherein the temperature is about 40° C. to about 60° C.
 15. Theprocess of claim 1, wherein the diastereomeric purity is at least 99.1%.16. The process of claim 1, wherein the diastereomeric purity is atleast 99.2%.
 17. The process of claim 1, wherein the diastereomericpurity is at least 99.5%.
 18. The process of claim 1, wherein thediastereomeric purity is at least 99.6%.
 19. The process of claim 1,wherein the diastereomeric purity is at least 99.9%.
 20. The process ofclaim 1, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 50%.
 21. The process ofclaim 1, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 90%.
 22. The process ofclaim 1, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 98%.
 23. The process ofclaim 4, wherein a salt form of d₆-6,7-dimethoxy-3,4-dihydroisoquinolineis reacted and the salt form is d₆-6,7-dimethoxy-3,4-dihydroisoquinolinehydrochloride.
 24. The process of claim 23, wherein the process iscarried out in the presence of K₂CO_(3.)
 25. The process of claim 24,wherein Xis halogen.
 26. The process of claim 25, wherein the halogen isiodide.
 27. The process of claim 26, wherein the diastereomeric purityis at least 99.1%.
 28. The process of claim 4, wherein Xis halogen. 29.The process of claim 28, wherein the halogen is iodide.
 30. The processof claim 4, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 50%.
 31. The process ofclaim 4, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 90%.
 32. The process ofclaim 4, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 98%.
 33. The process ofclaim 23, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 50%.
 34. The process ofclaim 23, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 90%.
 35. The process ofclaim 23, wherein the deuterium enrichment of the(RR,SS)-d₆-tetrabenazine is no less than about 98%.
 36. The process ofclaim 4, wherein a salt form of d₆-6,7-dimethoxy-3,4-dihydroisoquinolineis reacted and the salt form is d₆-6,7-dimethoxy-3,4-dihydroisoquinolinehydrochloride, X is iodide, and the diastereomeric purity is at least99.1.
 37. The process of claim 36, wherein the process is carried out inthe presence of K₂CO_(3.)